Chronic infections with the intracellular protozoan pathogen, Trypanosoma cruzi, lead to Chagas' disease in humans, the principal cause of heart failure in Latin America. Chagasic cardiomyopathy is characterized by chronic inflammation with associated hypertrophy and fibrosis. Preliminary findings from our laboratory have revealed the surprising observation that early in the infective process, a subset of host cell genes involved in fibrogenesis and extracellular matrix (ECM) remodeling is repressed by T. cruzi. The selectivity of this restricted host cell response to T. cruzi suggests that repression of the fibrogenic pathway may be advantageous to the parasite during the infectious process. Of particular interest is connective tissue growth factor (CTGF), a fibrogenic cytokine that promotes wound healing by inducing collagen and fibronectin synthesis and ECM deposition. Infective stages of T. cruzi were shown to secrete a stable, soluble factor that antagonizes TGFbeta-dependent induction of CTGF gene expression. In this pro posed study, T. cruzi-induced modulation of CTGF gene expression will be used as a sensitive reporter for the fibrogenic process. Molecular, biochemical and cellular approaches will be utilized to identify the signaling components involved in the modulation of the fibrogenic pathway during T. cruzi infection. These include specific parasite factors that mediate this process as well as host cell signaling pathways and receptor(s). Furthermore, we will carry out a detailed molecular characterization of T. cruzi-dependent modulation of the host fibrogenic pathway during acute experimental infections in mice. This system provides a solid experimental approach that will enable us to connect early signaling events triggered in host cells by T. cruzi to downstream effects on host cell gene expression, establishment of infection and pathogenesis of Chagas' disease. Characterization of the fibrogenic response in the context of infectious disease pathogenesis has broader implications for molecular mechanisms underlying fibrosis in disease states that do not have an infectious etiology. The potential far-reaching benefits of this research are apparent when considering that repression of CTGF during T. cruzi infection is mediated by a stable soluble parasite factor, which may have important therapeutic potential for a broad range of fibrotic disorders. [unreadable] [unreadable]